1. Field of the Invention
The invention relates generally to the conversion of xcex1,xcex2-unsaturated ketones and xcex1,xcex2-unsaturated esters to xcex1-hydroxy ketones and xcex1-hydroxy esters.
2. Description of Related Art
Methods for the conversion of xcex1,xcex2-unsaturated ketones and xcex1,xcex2-unsaturated esters to xcex1-hydroxy ketones and xcex1-hydroxy esters are known in the art. Conjugate reduction of xcex1,xcex2-unsaturated ketones using Na(MeOCH2CH2O)2AlH2/CuBr (Semmelhack et al., 1977); ((Ph3P)CuH)6 (Mahoney et al., 1988); ((Ph3P)CuH)6/n-Bu3SnH or PhSiH3 (Lipshutz et al., 1998); and PhSiH3/Mo(CO)6 (Keinan et al., 1987) are typically followed by oxidation at the xcex1-position to initially produce a mixture of xcex1-hydroperoxyketone and xcex1-hydroxyketone. The hydrosilylation of enones was done by Ojima et al. (1975). Fexe2x80x94H based reagents were used by Noyori et al. (1972), Cainelli et al, (1973), Yamashita et al., (1975), and Collman et al. (1978). For a general review of conjugate reductions, see Comprehensive Organic Synthesis, Vol 8. p. 523. Ed Trost, B. M.; Fleming, I. Pergamon Press, 1991.
In 1990 Inoki et al. reported a single step method for converting an xcex1,xcex2-unsaturated ester into an xcex1-hydroxy ester. A number of simple xcex1,xcex2-unsaturated esters were treated with a catalytic amount of what was believed to be bis(dipivaloylmethanato) manganese(II) (abbreviated to Mn(dpm)2)/PhSiH3/O2) in isopropanol at 0xc2x0 C., and obtained (after work-up with aqueous Na2S2O3) the saturated xcex1-hydroxyester in good yield.
One economically important conversion is the conversion of 16-dehydroprogesterone 3 into 17 xcex1-hydroxyprogesterone 4. This transformation of an xcex1,xcex2-unsaturated ketone to an xcex1-hydroxy ketone has been the subject of a number of patents (U.S. Pat Nos. 3,056,809, 3,444,160) and papers (Bailey et al., 1962). However, in each of these cases, a multi-step route was undertaken for the conversion.
17 xcex1-hydroxyprogesterone is a synthetic replacement for progesterone and is commonly used as a contraceptive and has a number of other uses in hormonal treatments. Therefore, there is a need for a method that is able to produce 17 xcex1-hydroxyprogesterone and other xcex1-hydroxyketones and esters using a single step.
A route for the conversion to xcex1,xcex2-unsaturated ketones or xcex1,xcex2-unsaturated esters to xcex1-hydroxy ketones or xcex1-hydroxy esters which requires only a single step under mild reaction conditions would be advantageous over the art. Known reaction routes for this conversion use basic conditions which cause the formation of 17-keto derivatives and ring D-homo rearrangements. They also involve a number of different steps which will often cause a decrease in yield or an increase in cost. It would therefore be desirable to have a method for converting xcex1,xcex2-unsaturated ketones or xcex1,xcex2-unsaturated esters into an xcex1-hydroxy ketones or xcex1-hydroxy esters that does not have these limitations.
This invention involves a method for converting xcex1,xcex2-unsaturated ketones and xcex1,xcex2-unsaturated esters into an xcex1-hydroxy ketones or xcex1-hydroxy esters. xcex2,xcex2-disubstituted ketones or esters can also be converted by the method of this invention. The reaction operates at neutral reaction conditions that prevent the formation of side reactions in a single step, which proceeds with excellent selectivity and gives a yield that is approximately 30% higher than the currently used processes. The conversion comprises: obtaining said xcex1,xcex2-unsaturated ketone or ester; obtaining a catalyst; obtaining a reducing agent; combining said ketone or ester, said catalyst and said reducing agent in the presence of dioxygen and a solvent or solvent mixture to form an xcex1-hydroperoxyketone or xcex1-hydroperoxyester; and reducing said xcex1-hydroperoxyketone or ester to an xcex1-hydroxyketone or ester with a reductive work-up.
The catalyst of this invention is of the structure: 
where each R is independently hydrogen, a C1-C20 linear branched or cyclic alkyl, hydroxyalkyl, glycol, polyglycol, amino, nitro, halo, cyano, aryl, heteroaryl, thio, thioalkyl, amide, ester, acyl, or carboxy. In a preferred embodiment of the invention, each R of the catalyst is the same and R is C1-C4 linear or branched alkyl. Preferably, at least one R is xe2x80x94H, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH2(CH3)2, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH2(CH3)CH2CH3, xe2x80x94CH2CH2(CH3)2, CH2(CH3)3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94OCH3, xe2x80x94O(CH2)nCH3, wherein n=0-20, and xe2x80x94CO(CH2)n wherein n=0-20. In a preferred embodiment of the invention, at least one R is xe2x80x94O(CH2)nCH3 and 0xe2x89xa6nxe2x89xa620, or more preferably xe2x80x94OCH3. In yet another embodiment, at least one R is NRxe2x80x22 and Rxe2x80x2 is hydrogen or C1-C20 linear, branched or cyclic alkyl, or more preferably xe2x80x94NH2. In the most preferred embodiment of the invention, the catalyst is tris(dipivaloylmethanato)manganese(III).
The reducing agent can be a silane, or more preferred diphenyl silane or polymethylhydrosiloxane. The most preferred reducing agent is phenyl silane.
The reductive work-up can include any reaction that causes the reduction of an xcex1-hydroperoxyketone or ester to an xcex1-hydroxyketone or ester. The preferred reducing agent is P(OEt)3 or P(OMe)3.
Solvents contemplated for this invention include alcohols such as isopropanol, tert-butyl alcohol or a mixture of an alcohol and another solvent such as 1,2-dichloroethane, dichloromethane or methylene chloride.
The substrate can be any xcex1,xcex2-unsaturated ketone or xcex1,xcex2-unsaturated ester. The carbon of the xcex1,xcex2-unsaturated ketone or ester can be part of a ring system. A preferred xcex1,xcex2-unsaturated ketone is 16-dehydroprogesterone.
Reaction conditions such as temperature, pressure, and time of the reaction may vary. The preferred temperature is between 0xc2x0 C. and 25xc2x0 C.
Contemplated in this invention is the conversion of 16-dehydroprogesterone to 17 xcex1-hydroxy progesterone comprising: obtaining said xcex1,xcex2-unsaturated ketone or ester; obtaining a catalyst of the structure: 
where R is described above; obtaining a reducing agent; combining said ketone or ester, said catalyst and said reducing agent in the presence of dioxygen and a solvent or solvent mixture to form an xcex1-hydroperoxyketone; and reducing said xcex1-hydroperoxyketone to an xcex1-hydroxyketone.
Another aspect of this invention is the reduction of xcex2,xcex2-disubstituted ketone or ester comprising: i) obtaining said xcex2,xcex2-disubstituted ketone or ester; ii) obtaining the catalyst tris(dipivaloylmethanato)manganes(III); iii) obtaining a reducing agent; iv) combining said ketone or ester, said catalyst and said reducing agent in the presence of dioxygen and a solvent or solvent mixture to produce a hydridic reagent capable of reducing said xcex2,xcex2-disubstitued ketone or ester. Preferred xcex2,xcex2-disubstituted ketone or ester include xcex2-ionone and 16-methyl dehydroprogesterone.